IL-6, LIF, and TNF-alpha regulation of GM-CSF inhibition of osteoclastogenesis in vitro

Exp Cell Res. 2004 Mar 10;294(1):149-58. doi: 10.1016/j.yexcr.2003.11.009.


During pathological bone loss, factors that are both stimulatory and inhibitory for osteoclast differentiation are over-expressed. Despite the presence of inhibitory factors, osteoclast differentiation is significantly enhanced to bring about bone loss. To examine the hypothesis that stimulatory growth factors overcome the effects of inhibitory factors, we have examined the ability of IGF-I, IGF-II, IL-6, LIF, and TNF-alpha to overcome osteoclast differentiation inhibition by GM-CSF in vitro. Osteoclast numbers were significantly elevated by treatment with IGF-I, IGF-II, IL-6, LIF, or TNF-alpha alone whereas GM-CSF treatment of stromal cell and osteoclast co-cultures inhibited osteoclast formation. IL-6, LIF, or TNF-alpha, individually overcame GM-CSF inhibition whereas neither IGF-I nor IGF-II treatment overcame GM-CSF inhibition. Interestingly, GM-CSF addition with either IL-6 or TNF-alpha increased osteoclast numbers beyond that seen with either IL-6 or TNF-alpha alone. Combined treatment with TNF-alpha and IL-6 showed a significant increase in osteoclast numbers with GM-CSF addition. Examination of the impacts of these growth factors individually or in combinations on stromal cell M-CSF, RANKL, and OPG expression revealed a complex pattern involving alterations in the ratio of RANKL to OPG and/or M-CSF expression as candidate mechanisms of action.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Drug Synergism
  • Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Interleukin-6 / pharmacology*
  • Leukemia Inhibitory Factor
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Somatomedins / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Carrier Proteins
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Lif protein, mouse
  • Membrane Glycoproteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Somatomedins
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Receptor, Macrophage Colony-Stimulating Factor